Improve the local microcirculation

Occlusions of the precapillary arterioles (30-50 m diameter) and empty nutritional capillaries have been found to occur at increased frequency in the toes of patients who have CCLI (Conrad, 1968 Fagrell, 1973). Even the slightest pressure from a shoe may damage ischemic skin tissue and completely prevent blood from entering the nutritional skin capillaries, resulting in an ischemic ulcer (Figure 17.1). Consequently, efforts must be made to try to improve the opportunity for blood to enter these...

Changes Of Shear Stress In The Microcirculation

The precise level of shear stress in the microcirculation can only be approximately determined because of the disparity of vessel size and flow velocities, and the uncertainty of the value of local viscosity since hematocrit in the microcirculation decreases as a function of blood vessel size, requiring the correction developed by Lipowsky and Firrell (1986) for estimating local blood viscosity on the basis of systemic samples. One of the first well-defined differences in microvascular function...

Chemistry Composition And Production

The composition of Fluosol and the functions of its components are listed in Table 25.2. The principal PFC and oxygen carrier in Fluosol was perfluorodecali n (C10F18), a compound subsequently used widely in biological systems (Zuck and Riess, 1994 Lowe, 1999, 2003 Riess, 2000, 2001). Lesser quantities of a second PFC, perfluoro-n-tripropylamine, (C3F7)3N, were added to stabilize the emulsion against droplet growth by the process of molecular diffusion known as Ostwald ripening (see Chapter...

Alpha hemoglobin stabilizing protein AHSP

Two years ago, Mitchell Weiss and colleagues identified a 102 amino acid protein whose expression was induced by GATA-1, an essential erythroid transcription factor (Kihm et al., 2002). The expression of this protein progressively increases during normal human erythropoiesis to levels of 0.1 mM in pro-erythroblasts (dos Santos et al., 2004). The protein binds isolated holo-a subunits reversibly with an association equilibrium constant equal to 10 M 1 and was named alpha hemoglobin stabilizing...

Tze Fei Wong PhD and Jan Blumenstein MD

Department of Biochemistry, Hong Kong University of Science & Technology, Clear Water Bay, Hong Kong, China *Dextro-Sang Corporation, Toronto, Canada In recent years the quest for a safe blood substitute has accelerated rapidly, propelled both by the hazardous nature of the blood supply in many parts of the world and by the increasingly satisfactory replacement of various plasma components with their recombinant counterparts. To replace the functions of erythrocytes and the bulk of plasma, a...

Facilitated Diffusion And Hyperoxygenation Of Arterioles

The PO2 distribution in the microcirculation decreases from 50 to 30 mmHg from A1 to A4 arterioles (Intaglietta et al., 1996). Using these values for PO2 and the parameters in the second term of Equation 5.6 DHbOl (AY Hb j Ax), we can calculate a theoretical amount of facilitated oxygen transfer in arteriolar vessels in the absence of biological compensatory mechanisms. For this exercise, we will compare two well-characterized hemoglobin solutions aa-Hb (Vandegriff et al., 1997 McCarthy et al.,...

The Future Of Perftoran

We completely agree with Keipert (2003) that the most likely anticipated future PFC emulsion application (which has already been demonstrated by preclinical and first clinical efficacy data) will target tissue ischemia, with a focus on the vital organs. Since Perftoran enhancement is limited by the probability of side effects (about 4 per cent), which frequently result from violated conditions of storage, the possibility of decreasing the frequency of these side effects by technological...

Considerations For Clinical Trials In Trauma

Many papers have been written about the pathophysiology of hemorrhagic shock and trauma, and medical interventions that might improve the clinical outcome following trauma (Moore et al., 2004). There have been a number of randomized clinical studies in this population to evaluate whether a given intervention improves outcome a number of these trials have demonstrated lack of effectiveness or resulted in negative safety findings with regard to the specific intervention ) under investigation...

Blood Plasma Serum And Albumin

The terms plasma and serum are frequently confused. Plasma refers to the liquid that suspends the red cells within the body. Serum is that liquid, removed from the body, from which the coagu-lum has been extracted. This is a very important distinction, because serum contains no coagulation factors and is severely depleted of platelets. As early as 1871 it was noted that a frog's heart could be maintained by perfusion with sheep and rabbit serum (Bowditch, 1871) and that this solution was...

Hema Gen and Oxyfluor

Shortly thereafter, HemaGen licensed Leland Clark's early technology and began supporting Dr Clark's research at the Children's Hospital Medical Center in Cincinnati. In 1986, HemaGen established a research laboratory to develop this technology further. In 1988, HemaGen sublicensed technology to Green Cross only for the Fluosol application (a formulation HemaGen had rejected) to enable it to enter the commercial market. In examining over 106 PFCs in emulsified...

Cardiac Function Output And Metabolism

The effects of HBOC-301 on ventricular systolic function and ventricular vascular coupling in normal dogs were investigated by Muir et al. (2000). Dogs received either 6 dextran 70 (control) or HBOC-301 at 15 ml kg. Control animals showed no significant differences during the experiment in heart rate, stroke volume, cardiac output systolic, diastolic and MAP systolic and diastolic left ventricular volume stroke work, dP dtmax end systolic elastance (Ees) or effective arterial elastance (Ea)....

Enrico Bucci PhD Barbara Matheson MD PhD Herman Kwansa PhD and Raymond C Koehler PhD

Department of Biochemistry and Molecular Biology, University of Maryland Medical School, Baltimore, Maryland, USA *Department of Biomedical Science, University of Maryland Dental School, Baltimore, Maryland, USA **Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA Three main problems affect the development of physiologically competent cell-free, hemoglobin-based oxygen carriers (HBOC). First, the loss of 2,3 BPG upon hemolysis...

History And Background

It has been recognized for many years that hemolysis or rhabdomyolysis causes kidney failure. Renal tubules became filled with hemoglobin or myoglobin pigment, hence the term 'pigment nephrosis'. Most research into the renal toxicity of hemoglobin has focused on the acute effects within hours of administering hemoglobin or heme to animals. In 1967, the observation that highly purified hemoglobin is less toxic than hemolyzed red blood cells (Rabiner et al., 1967) led to a decade of optimistic...

Eosinophils

Eosinophils are a type of white blood cell (comprising about 1-4 per cent of the peripheral leukocytes) that is recruited from the peripheral circulation into the tissue, and is especially prominent at sites of allergic reactions and parasite infections. These immune cells contain a bi-lobed nucleus and ellipsoid cytoplasmic granules. The granules each have an electron-dense, crystalline nucleus, and are composed of toxic, cationic proteins. When activated, eosinophils disrupt and deposit their...

Blood Circulation And Transfusion

The lore of blood transfusion is rooted in antiquity. Leviticus 7 26, which forbids the eating of blood, is the basis today for the refusal by certain religious groups to receive transfusions. However, the ancient Egyptians used 'blood baths' as a restorative, and Romans apparently rushed into the arenas to drink the blood of dying gladiators. However, no transfusion could occur until the circulation of the blood was understood. Although Ibn Nafis described the pulmonary circulation in the...

Editors Summary

Phase I studies in normal volunteers demonstrated a disappearance half-time from plasma of about 20 hours, and the data fit a single compartment model. The product was well tolerated, although there were 'minor' incidents of elevated blood pressure and gastrointestinal complaints as well as some elevations of liver enzymes and lipase. An interesting study of hemodynamics in normal volunteers given approximately 350 ml of HBOC-201 reported increased blood pressure, and decreased heart rate and...

Other Effects Of Crystalloid Infusion

Trauma, surgery and hemorrhage stimulate the immune system.Trauma with hemorrhagic shock activates neutrophils, and stimulates neutrophil adherence and migration. Although these responses are necessary to resist infection in traumatized tissue, excessive inflammatory responses can lead to ARDS and multiorgan failure. Infusion of LR, in comparison to infusion of blood or hypertonic saline, stimulated a burst of neutrophil activity in rats with hemorrhagic shock (Rhee et al., 1998, 2000) and was...

Critical properties revisited

Hemodilution with conventional colloids does not induce vasoconstriction. On the other hand, hemodilution with most of the Hb-based oxygen carriers, except Hbv-PEG5K10, causes varying degrees of hypertension. The colloidal osmotic pressure and viscosity of Hbv-PEG5K10 are higher than those of other Hb-based oxygen carriers but comparable to those of many plasma expanders in clinical use, such as the starches. This comparison suggested that the paradigm for the design of Hb-based oxygen carriers...

Potential Clinical Benefits Of Hbocs In Surgical Care

The potential benefits of HBOCs in surgical care can be categorized into the areas of availability, safety and efficacy (Table 13.1). Perhaps most conspicuous in the management of the patient with acute blood loss is the scenario when stored blood is not available. The logistic problems of access to typed cross-matched packed red blood cells (RBCs) for civilian trauma and the compelling need for an HBOC in military trauma is outlined in Chapter 12. There are patients whose demise is...

Animal models of acute and chronic toxicity

Currently there is no information about the acute effects of HBOCs on the renal vasculature and their long-term effects on tubulo-interstitial inflammation and scarring. Nor is there information about the effects of HBOCs on animals with acute tubular necrosis that simulates the human disease. These deficits should be rectified by observing the acute and chronic effects of HBOCs in animal models that more closely mimic human acute renal failure. Micro cDNA gene arrays are now being used to...

Further research on fluorocarbon emulsions and applications

Pfcs Blood Transfusion

Droplet coalescence in PFC and HC emulsions stabilized by water-soluble poloxamers or a bis(F-alkylated) polyethylene glycol (PEG) has Figure 24.13 Due to extremely low water solubility, volatile fluorocarbons can stabilize injectable oxygen microbubbles against rapid dissolution. Figure 24.13 Due to extremely low water solubility, volatile fluorocarbons can stabilize injectable oxygen microbubbles against rapid dissolution. been investigated (Shchukin et al., 2001). Droplet resistance to...

Apoglobin stability and expression

The mechanisms controlling oxygen affinity and NO dioxygenation are well understood and can be used to engineer safer and more effective O2 transporters. In contrast, the factors governing holohemoglobin expression in E. coliare not well understood. Over 10 years ago, we discovered that sperm whale apomyoglobin is 20-100 times more resistant to guanidinium chloride (GdmCl)-induced denaturation than most other mammalian apoMbs (Figure 31.7A Hargrove et al., 1994 Scott et al., 2000). This...

Vasoactivity Of Pegmodified Hemoglobin

Preclinical data using a number of potential Hb-based oxygen carriers have demonstrated hypertension as the most common and serious toxic effect of these products Hess et al., 1993 Thompson et al., 1994 . Overcoming the vasoac-tivity of acellular Hb has been the major obstacle in realizing the potential therapeutic application of the Hb-based oxygen carriers. The vasoactivity of Hb has, at least in part, been attributed to its nitric oxide scavenging activity. Two main approaches advanced to...

Reduction of allogeneic RBC transfusions

Prompted by the FDA guidelines to demonstrate efficacy, all HBOC companies have pursued what appeared to be the simplest clinically - i.e., to reduce the need for allogeneic RBC transfusions. In collaboration with David B. Hoyt, MD, and the University of California at San Diego, we conducted a randomized trial in patients requiring urgent transfusion Gould et al., 1998 . The 44 trauma patients Injury Severity Score ISS 21 1.3 were allocated to receive stored RBCs or up to 6 units of PolyHeme as...

Gum saline

Gum is a galactosidogluconic acid whose molecular mass is approximately 1500 Daltons. First used by Karl Ludwig in kidney perfusion experiments, gum-saline enjoyed great popularity as a plasma expander from the end of World War I onward. However, the aggregation state of gum depends on concentration, pH, salts and temperature thus, its colloid osmotic pressure and viscosity are quite variable. Conditions under which the viscosity would be the same as that of whole blood were identified by...

Oxygen Delivery Oxygen Uptake And The Critical Oxygen

Critical Do2

A useful way to consider the limits of compensation was introduced by Cain and his co-workers Cain, 1977 . They compared the delivery of oxygen DO2, cardiac output x arterial oxygen Figure 4.4 The critical DO2. As the hematocrit is reduced in 5 per cent steps, VO2 is maintained by a combination of rising cardiac output and falling PvO2, resulting in a larger fractional oxygen extraction. When these compensations no longer suffice to satisfy tissue oxygen requirements, metabolic work cannot be...

Requirements For A Blood Substitute

Some of the required properties of red cell substitutes are obvious. They must be sterile, free of endotoxin and viruses, non-toxic and efficacious, and it must be possible to store them for reasonable periods. The methods used to produce them must be tractable for industrial scale-up, and not too expensive. Lot-to-lot variation and immunogenicity must be minimal.These requirements can pose serious industrial problems, particularly when large batches must be prepared in a routine fashion. Some...

World War Ii

The Cook County Hospital in Chicago is often credited with establishing the first modern blood bank in 1937 Diamond, 1965 , although the Rowan Memorial Hospital in Salisbury, North Carolina established a plasma storage facility in 1935 Schmidt, 2000 . At the time, efforts were directed at the collection and storage of both liquid and dried plasma in anticipation of wartime use, after a plea from the British Red Cross in 1940 that the American National Red Cross should send plasma for use there....

Use Of Crystalloid Fluids In Surgical Procedures

The strategy of using crystalloids without colloid for replacement of fluid losses during elective surgical procedures continues to be controversial. In experimental animals subjected to hemorrhagic shock Shires et al., 1960, 1961 and traumatized patients Shires et al., 1961, 1964 , Shires et al. described substantial decreases in 'functional' extracellular volume, which they explained as sequestration within traumatized tissue, bowel and peritoneum. They recommended replacement with generous...

Mechanotransduction And Mechanosensors

A number of endothelial mechanosensors have been proposed, including caveolin caveolae, integrins, the cytoskeleton, PECAM-1 CD31 , the phospholipid membrane and the glycocalyx. However, the primary mechanosensor which transduces this mechanical stimulus into a biochemical signal remains unknown Davies, 1995 . Caveolin has been implicated as the endothelial mechanosensor for the activation of caveolin-associated MAP kinase and eNOS in a rat lung perfusion model Oh and Schnitzer, 2001 . These...

Cardiac Output

Asanguineous fluids expand vascular volume and increase cardiac output, but dilute red blood cells and oxygen content. Resuscitation with standard 'clear' IV fluids can increase cardiac output several fold, thereby effectively increasing oxygen delivery from depressed levels associated with shock to normal or even supranormal levels. Augmentation of supranormal levels of cardiac output with standard fluid resuscitation often occurs without full restoration of blood pressure, presumably because...

Tissue Oxygen Supply And Demand

Content Po2

Under normal circumstances oxygen delivery to various organs is more than adequate to meet the requirements for oxidative metabolism. Measurements in microcirculatory preparations primarily muscle from a number of laboratories indicate that PO2 in the interstitial fluid of resting tissue is generally between 20 and 30 mmHg Tsai et al., 2003 .These measurements include tissue regions at the venous end of the capillary network, where the oxygen tension is expected to be lowest. By contrast, the...

Introduction

Hemoglobin-based oxygen carriers have been under development for several decades for use in situations of blood loss and circulatory collapse. The primary stumbling block in the last few decades has been vasoconstriction, leading to capillary shutdown. Hemoglobin solutions with high oxygen-carrying capacity and an oxygen affinity similar to or lower than that of blood have long been reported to cause hypertension, reduced cardiac output and increased vascular resistance Hess et al., 1993...

Crystalloid Solutions

A crystalloid solution contains small particles that are composed of low molecular weight solutes lt 30 000 D that can be either ionic e.g. Na , CT or non-ionic e.g. glucose, mannitol . Crystalloid fluids are inexpensive compared with blood products and artificial colloids. The contents of a number of commonly used crystalloids are listed in Table 11.1. The systemic distribution of crystalloids is dependent on the amount of sodium in the solution. Solutions that contain approximately isotonic...

The Optimal Hematocrit

What is the 'optimal' hematocrit Obviously, there is no simple answer to this question and certainly none that would apply to all patients. Because it is easily measured, hematocrit is frequently taken as a surrogate for oxygen transport capa-bility.The bulk viscosity of blood increases exponentially with hematocrit, and increased viscosity raises resistance to blood flow, limiting cardiac output in the absence of compensatory mechanisms. As the oxygen capacity of the blood hemoglobin or...

References

S., Handrigan, M. T. et al. 2003 . Prolonged permissive hypotensive resuscitation in an awake rat model of hemorrhagic shock. Fed. Am. Soc. Exper. Biol. J., 17, A806.18. Bickell, W. H., Matthew, J., Wall, M. J. Jr et al. 1994 . Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. N. Engl. J. Med., 331, 1105-1109. Brauer, K. I., Prough, D. S., Traber, D. L. et al. 1999a . Large volume infusion of lactated Ringer's LR...

The Hemoglobin Oxygen Equilibrium Curve

Autoregulation of the oxygen supply insures that the organism adapts to moderate changes Figure 7.2 Arteriolar diameter in conditions of hypoxia, normoxia and hyperoxia caused by changing the composition of inspired gases or FiO2. Changes from normal air inspiration determine significant changes in tissue perfusion as the microcirculation strives to regulate oxygen delivery. in blood properties, and therefore the efficacy of a blood substitute cannot be determined unequivocally unless it is...

Summary

Oxygen transport by hemoglobin, either packaged inside red blood cells or in a cell-free solution, is ruled by physical laws of molecular transport. Molecular diffusion provides a fundamental differentiation between how oxygen is transported physically by cellular versus acellular oxygen carriers or by different types of cell-free oxygen carriers. Red blood cells and intracellular hemoglobin have evolved to carry sufficient oxygen from the lungs to offload to respiring tissue. The system acts...

Requirements For Combat Casualty Care

In US trauma centers, large volumes of crystalloids, particularly lactated Ringer's solution RL , are used for resuscitation of hemorrhage. Since each liter of RL only expands blood volume by 20-30 per cent of infused volume, several liters 3-5 liters infused to replace 1 liter bled of fluid are required to restore near normal blood volume after a major hemorrhage Lamke and Liljedahl, 1976 Drobin and Hahn, 1999 T0ll0fsrud et al., 2001 . Such volumes are logistically untenable for most combat...

Traumaresuscitation

One of the most obvious clinical applications for hemoglobin-based red cell substitutes is in emergencies such as trauma. Among the factors that determine the long-term survival after resuscitation from hypovolemic shock is the duration of the shock state Baker et al., 1985 . Messmer and his colleagues Messmer, 1988 have conducted extensive studies of the microcirculation in shock, and have pointed out that under the influence of the sympathetic nervous system organ flow is redirected to...

Perfluorocarbons

Perfluorocarbon Mice

In 1966, Leland Clark and Frank Gollan demonstrated dramatically that a laboratory mouse Figure 1.2 Liquid-breathing mouse. The mouse is totally immersed in perfluorocarbon FC-80, butyltetrahydrofuran which has been saturated with oxygen by bubbling at room temperature. Such a mouse can survive liquid breathing for many hours From Clark, 1985 . Figure 1.2 Liquid-breathing mouse. The mouse is totally immersed in perfluorocarbon FC-80, butyltetrahydrofuran which has been saturated with oxygen by...

List of Contributors

Seetharama A.Acharya 39 , Albert Einstein Univ. School of Medicine, 1300 Morris Park Avenue, Bronx, NY, USA Paul Aebersold 3 , Division of Blood Applications, Center for Biologies Evaluation and Research, FDA, Rockville, MD, USA Abdu I.Alayash 18 , Center for Biologics Evaluation and Research - NIH Campus, FDA, Bethesda, MD, USA Vibhu Awasthi 43 , University of Texas Health Science Center at San Antonio, San Antonio, TX, USA Andrew D. Baines 20 , Department of Laboratory Medicine and...